2-aryl-substituted pyridines

ABSTRACT

The 2-aryl-substituted pyridines are prepared by reacting pyridylaldehydes with organometallic compounds and then selectively reducing the products. The 2-aryl-substituted pyridines are suitable as active compounds in medicaments, in particular in medicaments for the treatment of arteriosclerosis.

The present invention relates to 2-aryl-substituted pyridines, toprocesses for their preparation and to their use in medicaments.

U.S. Pat. No. 5,169,857 discloses 7-(polysubstitutedpyridyl)-6-heptenoates for the treatment of arteriosclerosis,lipoproteinaemia and hyperproteinaemia. The preparation of7-(4-aryl-3-pyridyl)-3,5-dihydroxy-6-heptenoates is additionallydescribed in EP 325 130.

The present invention relates to 2-aryl-substituted pyridines of thegeneral formula (I) ##STR1## in which A and E are identical or differentand represent aryl having 6 to 10 carbon atoms, which is optionallysubstituted up to 3 times identically or differently by halogen,hydroxyl, trifluoromethyl, trifluoromethoxy or by straight-chain orbranched alkyl, acyl, hydroxyalkyl or alkoxy each having up to 7 carbonatoms, or by a group of the formula --NR¹ R²,

in which

R¹ and R² are identical or different and denote hydrogen, phenyl orstraight-chain or branched alkyl having up to 6 carbon atoms,

D represents straight-chain or branched alkyl having up to 8 carbonatoms, which is substituted by hydroxyl,

L represents cycloalkyl having 3 to 8 carbon atoms or straight-chain orbranched alkyl having up to 8 carbon atoms, which is optionallysubstituted by cycloalkyl having 3 to 8 carbon atoms or by hydroxyl,

T represents a radical of the formula ##STR2## in which R³ and R⁴ areidentical or different and denote cycloalkyl having 3 to 8 carbon atoms,or

denote aryl having 6 to 10 carbon atoms, or a 5- to 7-membered aromatic,optionally benzo-fused heterocycle having up to 3 heteroatoms from theseries S, N and/or O, each of which is optionally substituted up to 3times identically or differently by trifluoromethyl, trifluoromethoxy,nitro, halogen, hydroxyl, carboxyl, by straight-chain or branched alkyl,acyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or byphenyl, phenoxy or phenylthio, which for their part can be substitutedby halogen, trifluoromethyl or trifluoromethoxy,

and/or the cycles are optionally substituted by a group of the formula--NR⁷ R⁸,

in which

R⁷ and R⁸ are identical or different and have the meaning of R¹ and R²indicated above,

X denotes straight-chain or branched alkyl or alkenyl each having 2 to10 carbon atoms, each of which is optionally substituted up to 2 timesby hydroxyl or halogen,

R⁵ denotes hydrogen and

R⁶ denotes hydrogen, halogen, azido, trifluoromethyl, mercapto,hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy having upto 5 carbon atoms or a radical of the formula --NR⁹ R¹⁰,

in which

R⁹ and R¹⁰ are identical or different and have the meaning of R¹ and R²indicated above,

or

R⁵ and R⁶ together with the carbon atom form a carbonyl group,

and their salts.

The 2-aryl-substituted pyridines according to the invention can also bepresent in the form of their salts. In general, salts with organic orinorganic bases or acids may be mentioned here.

In the context of the present invention, physiologically acceptablesalts are preferred. Physiologically acceptable salts of the compoundsaccording to the invention can be salts of the substances according tothe invention with mineral acids, carboxylic acids or sulphonic acids.Particularly preferred salts are, for example, those with hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid,benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid,propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid,maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts ofthe compounds according to the invention, which have a free carboxylgroup. Particularly preferred salts are, for example, sodium, potassium,magnesium or calcium salts, and also ammonium salts which are derivedfrom ammonia, or organic amines, such as, for example, ethylamine, di-or triethylamine, di- or triethanolamine, dicyclohexylamine,dimethylaminoethanol, arginine, lysine, ethylenediamine or2-phenylethylamine.

The compounds according to the invention can exist in stereoisomericforms which either behave as image and mirror image (enantiomers), orwhich do not behave as image and mirror image (diastereomers). Theinvention relates both to the enantiomers or diastereomers and to theirrespective mixtures. These mixtures of the enantiomers and diastereomerscan be separated into the stereoisomerically uniform constituents in aknown manner.

Heterocycle, optionally benzo-fused, in the context of the invention ingeneral represents a saturated or unsaturated 5- to 7-membered,preferably 5- to 6-membered heterocycle, which can contain up to 3heteroatoms from the series S, N and/or O. Examples which may bementioned are: indolyl, isoquinolyl, quinolyl, benzo b!thiophene,benzothiazolyl, benzo b!furanyl, pyridyl, thienyl, furyl, pyrrolyl,thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Quinolyl,indolyl, pyridyl and benzothiazolyl are preferred.

Preferred compounds of the general formula (I) are those in which

A and E are identical or different and represent phenyl or naphthyl,each of which is optionally substituted up to 2 times identically ordifferently by fluorine, chlorine, bromine, hydroxyl, trifluoromethyl,trifluoromethoxy, nitro or by straight-chain or branched alkyl, acyl oralkoxy each having up to 6 carbon atoms or by a group of the formula--NR¹ R²,

in which

R¹ and R² are identical or different and denote hydrogen, phenyl orstraight-chain or branched alkyl having up to 4 carbon atoms,

D represents straight-chain or branched alkyl having up to 7 carbonatoms, which is substituted by hydroxyl,

L represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl,

or represents straight-chain or branched alkyl having up to 6 carbonatoms, which is optionally substituted by cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or by hydroxyl,

T represents a radical of the formula ##STR3## worin, in which

R³ and R⁴ are identical or different and denote cyclopropyl, cyclopentylor cyclohexyl, or denote naphthyl, phenyl, pyridyl, quinolyl, indolyl,benzothiazolyl or tetrahydronaphthalenyl, each of which is optionallysubstituted up to 3 times identically or differently by trifluoromethyl,trifluoromethoxy, fluorine, chlorine, bromine, hydroxyl, carboxyl, bystraight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl eachhaving up to 5 carbon atoms or by phenyl, phenoxy or phenylthio, whichfor their part can be substituted by fluorine, chlorine, bromine,trifluoromethyl or trifluoromethoxy,

and/or the cycles are optionally substituted by a group of the formula--NR⁷ R⁸,

in which

R⁷ and R⁸ are identical or different and have the meaning of R¹ and R²indicated above,

X is straight-chain or branched alkyl or alkenyl each having 2 to 8carbon atoms, each of which is optionally substituted up to 2 times byhydroxyl or fluorine,

R⁵ denotes hydrogen and

R⁶ denotes hydrogen, fluorine, chlorine, bromine, azido,trifluoromethyl, hydroxyl, mercapto, trifluoromethoxy, straight-chain orbranched alkoxy having up to 4 carbon atoms or a radical of the formula--NR⁹ R¹⁰,

in which

R⁹ and R¹⁰ are identical or different and have the meaning of R¹ and R²indicated above,

or

R⁵ and R⁶ together with the carbon atom form a carbonyl group, and theirsalts.

Particularly preferred compounds of the general formula (I) are those inwhich

A and E are identical or different and represent phenyl or naphthyl,each of which is optionally substituted up to 2 times identically ordifferently by fluorine, chlorine, bromine, hydroxyl, trifluoromethyl,trifluoromethoxy, nitro or by straight-chain or branched alkyl or alkoxyeach having up to 5 carbon atoms,

D represents straight-chain or branched alkyl having up to 6 carbonatoms, which is substituted by hydroxyl,

L represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl,

or represents straight-chain or branched alkyl having up to 5 carbonatoms, which is optionally substituted by cyclopentyl or cyclohexyl,

T represents a radical of the formula ##STR4## in which R³ and R⁴ areidentical or different and denote cyclopropyl, phenyl, pyridyl,quinolyl, indolyl, naphthyl, benzothiazolyl or tetrahydronaphthalenyl,each of which is optionally substituted up to 2 times identically ordifferently by trifluoromethyl, trifluoromethoxy, fluorine, chlorine,bromine, hydroxyl, carboxyl, amino, by straight-chain or branched alkyl,alkoxy or alkoxycarbonyl each having up to 4 carbon atoms or by phenyl,phenoxy or phenylthio, which for their part can be substituted byfluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy,

X denotes straight-chain or branched alkyl or alkenyl having 2 to 6carbon atoms, each of which is optionally substituted up to 2 times byhydroxyl or fluorine,

R⁵ denotes hydrogen and

R⁶ denotes hydrogen, fluorine, chlorine, bromine, azido,trifluoromethyl, amino, hydroxyl, trifluoromethoxy, methoxy or mercapto,

or

R⁵ and R⁶ together with the carbon atom form a carbonyl group, and theirsalts.

Very particularly preferred compounds of the general formula (I)according to the invention are those in which

A represents phenyl, which is optionally substituted up to 2 timesidentically or differently by fluorine, chlorine, methyl, nitro ormethoxy.

A process for the preparation of the compounds of the general formula(I) according to the invention has additionally been found,characterized in that compounds of the general formula (II) or (III)##STR5## in which A, E, L and T have the meaning indicated above and

R¹¹ represents straight-chain or branched alkoxycarbonyl having up to 4carbon atoms,

are either reacted first with organometallic reagents, in particularGrignard or Wittig reagents, in inert solvents, further derivatizationis optionally carried out according to customary methods and theproducts are then reduced in inert solvents, or in the case of thecompounds of the general formula (III) direct reductions, optionally bymeans of several stages, are carried out.

The processes according to the invention can be illustrated by way ofexample by the following reaction scheme: ##STR6##

Suitable solvents are ethers such as diethyl ether, dioxane,tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene,toluene, xylene, hexane, cyclohexane or petroleum fractions, orhalogenohydrocarbons such as dichloromethane, trichloromethane,tetrachloromethane, dichloroethylene, trichloroethylene orchlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethylsulphoxide, dimethylformamide, hexamethylphosphoramide, acetonitrile,acetone or nitromethane. It is also possible to use mixtures of thesolvents mentioned. Dichloromethane is preferred.

Suitable organometallic reagents are, for example, Grignard systems suchas Mg/bromobenzotrifluoride and p-trifluoromethylphenyllithium. Thesystem Mg/bromobenzotrifluoride is preferred.

The reductions and the derivatizations are carried out according to theabove-mentioned methods.

The reductions are in general carried out in ethers, such as, forexample, dioxane, tetrahydrofuran or diethyl ether or in hydrocarbonssuch as, for example, benzene, hexane or toluene. Toluene andtetrahydrofuran are preferred.

Suitable reducing agents are complex metal hydrides, such as, forexample, lithium aluminium hydride, sodium cyanoborohydride, sodiumaluminium hydride, diisobutylaluminium hydride, dimethoxymethylaluminatesodium salt or sodium bis-(2-methoxyethoxy)dihydroaluminate (Red-Al).Diisobutylaluminium hydride (DIBAL-H) and dimethoxymethylaluminatesodium salt are preferred.

The reducing agent is in general employed in an amount from 4 mol to 10mol, preferably from 4 mol to 5 mol, relative to 1 mol of the compoundsto be reduced.

The reduction in general proceeds in a temperature range from -78° C. to+50° C., preferably from -78° C. to 0° C., particularly preferably at-78° C., in each case depending on the choice of the reducing agent andsolvent.

The reduction in general proceeds at normal pressure, but it is alsopossible to work at elevated or reduced pressure.

The reductions can however also be carried out using reducing agentswhich are suitable for the reduction of ketones to hydroxy compounds.Particularly suitable in this case is reduction with metal hydrides orcomplex metal hydrides in inert solvents, if appropriate in the presenceof a trialkylborane. Preferably, the reduction is carried out usingcomplex metal hydrides such as, for example, lithium borohydride, sodiumborohydride, potassium borohydride, zinc borohydride, lithiumtrialkylborohydride or lithium aluminium hydride. The reduction is veryparticularly preferably carried out using sodium borohydride, in thepresence of triethylborane.

The hydrogenation is carried out by customary methods using hydrogen inthe presence of noble metal catalysts, such as, for example, Pd/C, Pt/Cor Raney nickel in one of the abovementioned solvents, preferably inalcohols such as, for example, methanol, ethanol or propanol, in atemperature range from -20° C. to +100° C., preferably from 0° C. to+50° C., at normal pressure or elevated pressure.

Derivatizations which may be mentioned by way of example are thefollowing types of reaction:

oxidations, reductions, hydrogenations, halogenation, Wittig/Grignardreactions and amidations/sulphoamidations.

Possible bases for the individual steps are the customary strongly basiccompounds. These preferably include organolithium compounds such as, forexample, N-butyllithium, sec-butyllithium, tert-butyllithium orphenyllithium, or amides such as, for example, lithium diisopropylamide,sodium amide or potassium amide, or lithium hexamethylsilylamide, oralkali metal hydrides such as sodium hydride or potassium hydride.N-Butyllithium and sodium hydride are particularly preferably employed.

Suitable bases are additionally the customary inorganic bases. Thesepreferably include alkali metal hydroxides or alkaline earth metalhydroxides such as, for example, sodium hydroxide, potassium hydroxideor barium hydroxide, or alkali metal carbonates such as sodium orpotassium carbonate or sodium hydrogen carbonate. Sodium hydroxide andpotassium hydroxide are particularly preferably employed.

Suitable solvents for the individual reaction steps are also alcoholssuch as methanol, ethanol, propanol, butanol or tert-butanol.tert-Butanol is preferred.

It may be necessary to carry out some reaction steps under a protectivegas atmosphere.

The halogenations are in general carried out in one of theabovementioned chlorinated hydrocarbons, methylene chloride beingpreferred.

Suitable halogenating agents are, for example, diethylaminosulphurtrifluoride (DAST) or SOCl₂.

The halogenation in general proceeds in a temperature range from -78° C.to +50° C., preferably from -78° C. to 0° C., particularly preferably at-78° C., in each case depending on the choice of the halogenating agentand solvent.

The halogenation in general proceeds at normal pressure, but it is alsopossible to work at elevated or reduced pressure.

Suitable Wittig reagents are the customary reagents.3-Trifluoromethylbenzyltriphenylphosphonium bromide is preferred.

Suitable bases are in general one of the abovementioned bases,preferably Li bis-(triethylbutyl)amide.

The base is employed in an amount from 0.1 mol to 5 mol, preferably from0.5 mol to 2 mol, in each case relative to 1 mol of the startingcompound.

The reaction with Wittig reagents is in general carried out in atemperature range from 0° C. to 150° C., preferably at 25° C. to 40° C.

The Wittig reactions are in general carried out at normal pressure.However, it is also possible to carry out the process at reducedpressure or at elevated pressure (e.g. in a range from 0.5 to 5 bar).

The compounds of the general formula (II) are known or can be preparedby oxidizing compounds of the general formula (IV) ##STR7## in which A,E and L have the meaning indicated above,

R¹³ and R¹⁴ are identical or different and represent straight-chain orbranched alkyl having up to 4 carbon atoms,

with oxidizing agents in inert solvents

and

in a second step selectively reducing the alkoxycarbonyl function (CO₂R¹³) to the hydroxy function.

Suitable solvents for the oxidation are ethers such as diethyl ether,dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such asbenzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, orhalohydrocarbons such as dichloromethane, trichloromethane,tetrachloromethane, dichloroethylene, trichloroethylene orchlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethylsulphoxide, dimethylformamide, hexamethylphosphoramide, acetonitrile,acetone or nitromethane. It is also possible to use mixtures of thesolvents mentioned. Dichloromethane is preferred.

Suitable oxidizing agents are, for example,2,3-dichloro-5,6-dicyano-benzoquinone, pyridinium chlorochromate (PCC),osmium tetroxide and manganese dioxide.2,3-Dichloro-5,6-dicyano-benzoquinone (DDQ) is preferred for theabovementioned step.

The oxidizing agent is employed in an amount from 1 mol to 10 mol,preferably from 2 mol to 5 mol, relative to 1 mol of the compounds ofthe general formula (IV).

The oxidation in general proceeds in a temperature range from -50° C. to+100° C., preferably from 0° C. to room temperature.

The oxidation in general proceeds at normal pressure. However, it isalso possible to carry out the oxidation at elevated or reducedpressure.

The 1,4-dihydropyridine-3,5-dicarboxylic acid esters of the generalformula (IV) are known or can be prepared by known methods.

The compounds of the general formula (III) are for the most part new andare prepared by converting compounds of the general formula (V) ##STR8##in which A, E, L and T have the meaning indicated above and

R¹⁵ represents straight-chain or branched alkoxycarbonyl having up to 3carbon atoms,

first by reduction of the alkoxycarbonyl function into the compounds ofthe general formula (Ia) ##STR9## in which A, E, L and T have themeaning indicated above,

and in a second step oxidizing the hydroxymethyl function under theabovementioned conditions, preferably using pyridinium chlorochromate(PCC), to the aldehyde.

The individual reaction steps are in general carried out in atemperature range from -10° C. to +160° C., preferably from 0° C. to+100° C. and normal pressure.

The compounds of the general formula (V) are prepared in analogy to themethod described above for the preparation of the compounds of thegeneral formula (II).

The compounds of the general formula (Ia) are new and can be prepared asdescribed above.

The compounds of the general formulae (I) and (Ia) according to theinvention have an unforeseeable spectrum of pharmacological action.

The compounds of the general formulae (I) and (Ia) according to theinvention have useful pharmacological properties which are superior incomparison with the prior art, in particular they are highly effectiveinhibitors of cholesterol ester transfer protein (CETP) and stimulatereverse cholesterol transport. Reactive compounds according to theinvention cause a lowering of the LDL cholesterol level in the bloodwith simultaneous raising of the HDL cholesterol level. They cantherefore be employed primary and for the treatment ofhyperlipoproteinaemia, hypolipoproteinaemia, dislipidaemia,hypotriglyceridaemia, combined hyperlipidaemia or arteriosclerosis.

The invention additionally relates to the combination of2-aryl-substituted pyridines of the general formula (I) according to theinvention with a glucosidase and/or amylase inhibitor for the treatmentof familial hyperlipidaemias, obesity (adiposity) and diabetes mellitus.Glucosidase and/or amylase inhibitors in the context of the inventionare, for example, acarbose, adiposine, voglibose, miglitol, emiglitate,MDL-25637, camiglibose (MDL-73945), tendamistate, AI-3688, trestatin,pradimicin-Q and salbostatin.

The combination of acarbose, miglitol, emiglitate or voglibose with oneof the abovementioned compounds of the general formula (I) according tothe invention is preferred.

Furthermore, the invented compounds will be used in combination withcholesterol-lowering vastatins or ApoB-lowering drugs, to treatdyslipidemia, combined hyperlipidemia, hypercholesterolemia orhypertriglyceridemia. The mentioned combinations are also valid forprimary or secondary prevention of coronary artery disease.

Vastatins as covered by the inventions are for instance lovastatin,simvastatin, pravastatin, fluvastatin, atorvastatin or cerivastatin,ApoB lowering compounds could be MTP-inhibitors.

The combinations of cerivastin or ApoB-Inhibitors with one of the abovementioned compounds with the formula (I) are most favored.

The pharmacological action of the substances according to the inventionwas determined in the following test:

CETP inhibition testing

1. Obtainment of CETP

CETP is obtained in partially purified form from human plasma bydifferential centrifugation and column chromatography and used for thetest. To this end, human plasma is adjusted to a density of 1.21 g perml using NaBr and centrifuged at 4° C. for 18 h at 50,000 rpm. Thebottom fraction (d>1.21 g/ml) is applied to a Sephadex®phenyl-sepharose4B (Pharmacia) column, washed with 0.15M NaCl/0.001M trisHCl pH 7.4 andthen eluted with dist. water. The CETP-active fractions are pooled,dialysed against 50 mM Na acetate pH 4.5 and applied to a CM-Sepharose®(Pharmacia) column. The column is then eluted using a linear gradient(0-1M NaCl). The pooled CETP fractions are dialysed against 10 mMtrisHCl pH 7.4 and then further purified by chromatography on a Mono Q®column (Pharmacia).

2. Obtainment of radiolabelled HDL

50 ml of fresh human EDTA plasma is adjusted to a density of 1.12 usingNaBr and centrifuged for 18 h at 50,000 rpm at 4° C. in a Ty 65 rotor.The upper phase is used to obtain cold LDL. The lower phase is dialysedagainst 3×4 l of PDB buffer (10 mM tris/HCl pH 7.4, 0.15 mM NaCl, 1 mMEDTA, 0.02% NaN₃). 20 μl of ³ H-cholesterol (Dupont NET-725; 1 μC/μldissolved in ethanol) are then added per 10 ml of retentate volume andincubation is carried out at 37° C. under N₂ for 72 h.

The mixture is then adjusted to the density 1.21 using NaBr andcentrifuged at 20° C. at 50,000 rpm in the Ty 65 rotor for 18 h. Theupper phase is recovered and the lipoprotein fractions are purified bygradient centrifugation. To this end, the isolated, labelled lipoproteinfraction is adjusted to a density of 1.26 using NaBr. Each 4 ml of thissolution are covered with a layer of 4 ml of a solution of density 1.21and 4.5 ml of a solution of density 1.063 (density solutions of PDBbuffer and NaBr) in centrifuge tubes (SW 40 rotor) and then centrifugedin the SW 40 rotor for 24 h at 38,000 rpm and 20° C. The intermediatelayer containing the labelled HDL lying between the densities 1.063 and1.21 is dialyzed against 3×100 volumes of PDB buffer at 4° C.

The retentate contains radiolabelled ³ H-CE-HDL which, adjusted to about5×10⁶ cpm per ml, is used for the test.

3. Test procedure

For testing the CETP activity, the transfer of ³ H-cholesterol esterfrom human HD lipoproteins to biotinylated LD lipoproteins is measured.

The reaction is ended by addition of streptavidin-SPA® beads (Amersham)and the transferred radioactivity is determined directly in a liquidscintillation counter.

In the test mixture, 10 μl of HDL-³ H-cholesterol ester (˜50,000 cpm)are incubated at 37° C. for 18 h with 10 μl of biotin-LDL (Amersham) in50 mM Hepes/0.15 m NaCl/0.% bovine serum albumin/0.05% NaN₃ pH 7.4 with10 μl of CETP (1 mg/ml) and 3 μl of solution of the substance to betested (dissolved in 10% DMSO/1% RSA). 200 μl of the SPA-streptavidinbead solution (Amersham TRKQ 7005) are then added, the mixture isincubated further for 1 h with shaking and then measured in thescintillation counter. As controls, corresponding incubations with 10 μlof buffer, 10 μl of CETP at 4° C. and 10 μl of CETP at 37° C. are used.The activity transferred into the control mixtures with CETP at 37° C.is rated as 100% transfer. The substance concentration at which thistransfer is reduced by half is indicated as the IC₅₀ value.

In the following table, the IC₅₀ values (mol/l) are indicated for CETPinhibitors:

    ______________________________________    Example no.  IC.sub.50 value (mol/l)    ______________________________________    3            8 × 10.sup.-7    14           7 × 10.sup.-8    26           9 × 10.sup.-7    31           5 × 10.sup.-7    37           3 × 10.sup.-7    42           1.7 × 10.sup.-7 to 9 × 10.sup.-8    45           3 × 10.sup.-7    51           4 × 10.sup.-7    53           1.7 × 10.sup.-7    63           1.0 × 10.sup.-6    68           8 × 10.sup.-8    83           5 × 10.sup.-6    ______________________________________

Syrian golden hamsters from in-house breeding are anaesthetized afterfasting for 24 hours (0.80 mg/kg of atropine, 0.80 mg/kg of Ketavet®s.c. 30' later 50 mg/kg of Nembutal i.p.). The jugular vein is thenexposed and cannulated. The test substance is dissolved in a suitablesolvent (as a rule Adalat placebo solution: 60 g of glycerol, 100 ml ofH₂ O, PEG-400 to 1000 ml) and administered to the animals via a PEcatheter inserted into the jugular vein. The control animals receive thesame volume of solvent without test substance. The vein is then tied offand the wound is closed. After various times--up to 24 hours afteradministration of the test substance--blood (about 250 μl) is removedfrom the animals by puncture of the retro-orbital venous plexus.Clotting is concluded by incubation at 4° C. overnight, thencentrifugation is carried out at 6000 g for 10 minutes. In the serumthus obtained, the content of cholesterol and triglycerides isdetermined with the aid of modified commercially available enzyme tests(cholesterol enzymatic 14366 Merck, triglycerides 14364 Merck). Serum issuitably diluted using physiological saline solution.

100 μl of serum dilution are mixed with 100 μl of test substance in96-well plates and incubated at room temperature for 10 minutes. Theoptical density is then determined at a wavelength of 492 nm using anautomatic plate-reading apparatus (SLT Spectra). Thetriglyceride/cholesterol concentration contained in the samples isdetermined with the aid of a standard curve measured in parallel.

The determination of the content of HDL cholesterol is carried out afterprecipitation of the ApoB-containing lipoproteins by means of a reagentmixture (Sigma 352-4 HDL cholesterol reagent) according to themanufacturer's instructions.

In experiments to determine the oral activity, test substance dissolvedin DMSO and suspended in 0.5% Tylose is administered orally by means ofstomach tube to Syrian golden hamsters from in-house breeding. Thecontrol animals receive identical volumes of solvent without testsubstance. Feed is then withdrawn from the animals and at varioustimes--up to 24 hours after substance administration--blood is removedby puncture of the retroorbital venous plexus. Further processing iscarried out as described above.

Determination of the CETP activity

After intravenous administration of 20 mg/kg of the compound fromExample 42, an about 50% reduction of the CETP activity measured ex vivois found over a period of at least 2 hours. 24 hours after substanceadministration, the HDL cholesterol values in the substance-treatedgroup are about 30% higher than in the control group. Likewise, 24 hoursafter administration of 100 mg/kg per os of the compound from Example42, HDL cholesterol levels which are increased by 30% are found in thesubstance-treated group.

After administration of 2×45 mg/kg per os of the compound from Example44, the level of HDL cholesterol 24 hours after the first administrationis increased by 20% compared with the control group. At this time, thelevel of the triglycerides is lowered by 70% compared with the controlgroup.

The new active compounds can be converted in a known manner into thecustomary formulations, such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, non-toxic, pharmaceutically suitable excipients or solvents. Inthis case, the therapeutically active compound should in each case bepresent in a concentration of about 0.5 to 90% by weight of the totalmixture, i.e. in amounts which are sufficient in order to achieve thedosage range indicated.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or excipients, if appropriate usingemulsifiers and/or dispersants, where, for example, if water is used asa diluent, organic solvents can optionally be used as auxiliarysolvents.

Administration takes place in the customary manner, intravenously,parentally, perligually or orally, preferably orally.

In the case of parenteral administration, solutions of the activecompound using suitable liquid excipient materials can be employed.

In general, it has proved advantageous in the case of intravenousadministration to administer amounts of approximately 0.001 to 1 mg/kg,preferably approximately 0.01 to 0.5 mg/kg of body weight to achieveeffective results, and in the case of oral administration the dose isapproximately 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg of bodyweight.

In spite of this, it may, if appropriate, be necessary to depart fromthe amounts mentioned, mainly depending on the body weight or on thetype of administration route, on individual behaviour towards themedicament, the manner of its formulation and the time or interval atwhich administration takes place. Thus in some cases it may be adequateto manage with less than the abovementioned minimum amount, while inother cases the upper limit mentioned has to be exceeded. In the case ofthe administration of relatively large amounts, it may be advisable todivide these into several individual doses over the course of the day.

I. Eluents for TLC

A₁ =petroleum ether 40/60: ethyl acetate 4:1

A₂ =petroleum ether 40/60: ethyl acetate 6:1

A₃ =petroleum ether 40/60: ethyl acetate 9:1

A₄ =toluene

A₅ =toluene : ethyl acetate 9:1

A₆ =petroleum ether 40/60 : ethyl acetate 2:1

A₇ =petroleum ether : ethyl acetate 5:1

A₈ =toluene : ethyl acetate 7:3

A₉ =cyclohexane/tetrahydrofuran 8:2

A₁₀ =cyclohexane/tetrahydrofuran 9:1

A₁₁ =toluene: ethyl acetate 8:2

STARTING COMPOUNDS EXAMPLE I 3-Methyl 5-ethyl1,4-dihydro-2,4-di-(4-fluorophenyl)-6-isopropylpyridine-3,5-dicarboxylate ##STR10##

31 g (0.25 mol) of p-fluorobenzaldehyde, 49 g (0.25 mol) of methyl4-fluorobenzoylacetate and 39.25 g (0.25 mol) of ethyl3-amino-4-methyl-pent-2-enoate are boiled under reflux for 18 hours in150 ml of ethylene glycol at a bath temperature of 130° C. The mixtureis cooled to room temperature, extracted three times using 300 ml ofdiethyl ether, the combined ether phases are concentrated, and theresidue is dissolved in 100 ml of toluene and chromatographed on 700 mlof silica gel (0.04-0.063 mm) using toluene as an eluent.

Yield: 21.52 g (19.5% of theory)

R_(f) =0.29 (A₅)

Example II 3-Methyl 5-ethyl2,4-di-(4-fluorophenyl)-6-isopropyl-pyridine-3,5-dicarboxylate ##STR11##

3.08 g (13.59 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) areadded to a solution of 6.0 g (13.59 mmol) of the compound from Example Iin 180 ml of CH₂ Cl₂ p.a. and the mixture is stirred at room temperaturefor 1 h. The solid is then filtered off with suction through silica gel60, washed with 200 ml of CH₂ Cl₂, and the combined filtrates areconcentrated to give an oil, which is crystallized in petroleum ether.

Yield: 3.96 g (66.3% of theory)

R_(f) =0.54 (A₅)

Example III Methyl2,4-di-(4-fluorophenyl)-6-isopropyl-5-hydroxymethyl-pyridine-3-carboxylate ##STR12##

Under argon, 47.5 ml (0.166 mol, 2.05 eq.) of a 3.5-molar solution ofsodium bis-(2-methoxyethoxy)-dihydroaluminate (Red-Al) in toluene areslowly added to a solution of 34.5 g (0.0811 mol) of the compound fromExample II in 300 ml of THF p.a. and the mixture is stirred for 3 h. Thereaction solution is treated with ice-cooling with 150 ml of a 20%strength potassium sodium tartrate solution and extracted with 200 ml ofethyl acetate. The organic phase is washed once with saturated NaClsolution, dried over Na₂ SO₄ and concentrated in vacuo. The residue ischromatographed on silica gel 60, first with toluene, then with anincreasing proportion of ethyl acetate (toluene/ethyl acetate=9:1). Theeluates are concentrated and crystallized by triturating with petroleumether.

Yield: 12.8 g (39.8% of theory)

R_(f) =0.29 (A₅)

Example IV Methyl2,4-di-(4-fluorophenyl)-6-isopropyl-5-formylpyridine-3-carboxylate##STR13##

15.55 g (0.1525 mol; 2.0 eq.) of neutral Al₂ O₃ and 32.93 g (0.1525 mol;2 eq.) of pyridinium chlorochromate (PCC) are added to a solution of30.3 g (0.0762 mol) of the compound from Example III in 500 ml of CH₂Cl₂ and the mixture is stirred at room temperature for 1 h. The solid isfiltered off with suction through silica gel and washed with 600 ml ofCH₂ Cl₂, and the filtrate is concentrated in vacuo, the productcrystallizing out.

Yield: 13.9 g (90.1% of theory)

R_(f) =0.8 (A₁₁)

Example V Methyl 4,6-bis-p-fluorophenyl-2-isopropyl-3-(p-trifluoromethylphenyl)-hydroxymethyl!-pyridine-5-carboxylate##STR14##

215.8 mg (8.88 mmol) of magnesium turnings are initially introduced into30 ml of THF p.a., the mixture is heated to reflux under argon and 1.34ml (9.56 mmol; 1.4 eq.) of 4-bromobenzodifluoride are rapidly addeddropwise by means of a syringe. After an initially very violentreaction, the mixture is boiled under reflux for 30 min, it is thenallowed to cool to room temperature (Grignard reagent). 2.7 g (6.83mmol) of the compound from Example IV are dissolved in 20 ml of THFp.a., the solution is cooled to -78° C. under argon and then theGrignard reagent is added by means of a syringe. The mixture is thenstirred for 45 min without cooling. The reaction solution is partitionedin 250 ml of ethyl acetate/NH₄ Cl solution (1:1), the organic layer isseparated off and the aqueous layer is extracted twice with ethylacetate. The combined organic phases are dried over Na₂ SO₄ andconcentrated in vacuo. The oily residue is crystallized using petroleumether, filtered off with suction and dried in vacuo.

Yield: 2.55 g (69% of theory)

R_(f) =0.42 (A₅)

Example VI Methyl 2,4-di-(4-fluorophenyl)-6-isopropyl-5-4-(trifluorophenyl)-fluoromethyl!-pyridine-3-carboxylate ##STR15##

0.22 ml (1.66 mmol, 1.5 eq.) of diethylaminosulphur trifluoride (DAST)are added at -70° C. under argon to a solution of 600 mg (1.108 mmol) ofthe compound from Example V in 15 ml of CH₂ Cl₂ p.a. by means of asyringe, the cooling bath is removed and the mixture is stirred at -5°C. for 1 h. The reaction solution is then partitioned in ethylacetate/NH₄ Cl solution, the organic phase is separated off and theaqueous phase is washed once with ethyl acetate. The combined ethylacetate phases are dried over Na₂ SO₄ and concentrated in vacuo, and theresidue is crystallized by triturating with petroleum ether.

Yield: 359 mg (59.6% of theory)

R_(f) =0.79 (A₅)

Example VII Methyl 2,4-di-(4-fluorophenyl)-6-isopropyl-5-4-(trifluorophenyl)-chloromethyl!-pyridine-3-carboxylate ##STR16##

1.85 g (3.416 mmol) of the compound from Example V are dissolved in 500ml of CH₂ Cl₂ p.a. under argon and cooled to -40° C., and 0.745 ml(10.25 mmol; 3.0 eq.) of SOCl₂ are added dropwise by means of a syringe.The mixture is stirred for a further 30 min at -40° C. and the mixtureis then stored at -30° C. overnight. It is then stirred further at roomtemperature (35 min) until conversion is complete (TLC). The mixture ispoured onto 100 ml of saturated NaHCO₃ solution and 200 ml of ethylacetate, the organic phase is separated off, washed once with 50 ml ofsaturated NaHCO₃ solution, dried over Na₂ SO₄ and concentrated in vacuo,and the residue is crystallized by triturating with petroleum ether.

Yield: 1.42 g (74.6% of theory)

R_(f) =0.9 (A₅)

Example VIII Methyl 2,4-di-(4-fluorophenyl)-6-isopropyl-5-4-(trifluorophenyl)-azidomethyl!-pyridine-3-carboxylate ##STR17##

0.9 g (1.607 mmol) of the compound from Example VII and 1.044 g (16.07mmol; 10 eq.) of NaN₃ are stirred in 40 ml of DMSO for 4 h at 80° C. andthen for 12 h at room temperature. 100 ml of ethyl acetate are thenadded, and the mixture is washed once with water and three times withsaturated NaCl solution. The organic phase is dried over Na₂ SO₄ andconcentrated, and the residue is crystallized by triturating withpetroleum ether.

Yield: 370 mg (40.7% of theory)

R_(f) =0.81 (A₅)

Example IX Methyl 2,4-di-(4-fluorophenyl)-6-isopropyl-5-4-(trifluoromethylphenyl)-aminomethyl!-pyridine-3-carboxylate ##STR18##

630 mg (1.112 mmol) of the compound from Example VIII are hydrogenatedovernight at normal pressure and 20° C. using hydrogen in 40 ml of abs.CH₃ OH and 20 ml of abs. THF in the presence of 60 mg of Pd/C (10% ).The catalyst is then filtered off with suction through silica gel andwashed with methanol/THF (1: 1) and THF, and the solvent is distilledoff in vacuo. The residue is purified on 70 g of silica gel by columnchromatography using toluene and toluene/ethyl acetate (7:3).

Yields: 1st fraction=113 mg (18.8% of theory) 2nd fraction=296 mg (49.3%of theory)

R_(f) =0.13 (A₅)

Example X Methyl2,4-di-(4-fluorophenyl)-6-cyclopentyl-5-2-(benzothiazol-2-yl)-hydroxymethyl!-pyridine-3-carboxylate ##STR19##

1.04 ml (1.7 mmol) of butyllithium (1.6 molar in hexane) are added underargon at -78° C. to 230 mg (1.7 mmol) of benzothiazole in 20 ml of THFp.a. After stirring for 5 min at -78° C., a solution of 623 mg (1.478mol) of methyl2,4-di-(4-fluorophenyl)-6-cyclopentyl-5-formyl-pyridine-3-carboxylate in10 ml of THF p.a. is added dropwise. The temperature is then allowed toclimb from -78° C. to room temperature. The mixture is poured onto ethylacetate/NH₄ Cl solution with ice-cooling, and the organic phase iswashed once with saturated NaCl solution, dried over Na₂ SO₄ andconcentrated. After chromatography on 50 ml of silica gel using toluene,466 mg (56.7% of theory) are obtained.

R_(f) =0.33 (A₅)

Example XI Methyl 2,4-di-(4-fluorophenyl)-6-cyclopentyl-5-2-(benzothiazol-2-yl)-fluoromethyl!-pyridine-3-carboxylate ##STR20##

Analogously to Example VI, 439 mg (0.789 mmol) of the compound fromExample X are reacted with 190.7 mg (1.183 mmol; 1.5 eq.) of DAST in 30ml of CH₂ Cl₂ p.a.

Yield: 350 mg (79.5% of theory)

R_(f) =0.47 (A₅)

Example XII Methyl 2,4-di-(4-fluorophenyl)-6-isopropyl-5-2-(E/Z)-3-(trifluoromethyl-phenyl)vinyl-pyridine-3-carboxylate ##STR21##

1.755 g (3.5 mmol) of 3-trifluoromethylbenzyl-triphenylphosphoniumbromide are treated dropwise at 0° C. under argon in 10 ml of THF p.a.with 3.85 ml (3.85 mmol; 1.1 eq.) of lithium bis-(trimethylsilyl)amide(1.0 molar in hexane) in the course of 10 min and the mixture is stirredat 0° C. for 30 min. 1.246 mg (3.15 mmol; 0.9 eq.) of the compound fromExample IV in 2 ml of THF are then added dropwise in 10 min at 0° C. andthe mixture is stirred for 20 min at 0° C. and for 80 min withoutcooling. The reaction solution is treated with saturated NH₄ Cl solutionand extracted three times with 40 ml of ethyl acetate each time. Thecombined ester phases are dried over Na₂ SO₄ and concentrated in vacuo.The residue is chromatographed on 60 ml of silica gel 60 using toluene.

Yield: 1.22 g (72.1% of theory)

R_(f) =0.77 (A₄)

Example XIII Methyl 2,4-di-(4-fluorophenyl)-6-isopropyl-5-2-(3-(trifluoromethyl-phenyl)-1,2-dihydroxyethyl!-pyridine-3-carboxylate##STR22##

A mixture of 300 mg (0.559 mmol) of the compound from Example XII, 141mg (1.2 mol; 2.1 eq) of N-methylmorpholine-N-oxide and 2.1 ml (0.168mmol) of a 2.5% strength osmium tetroxide solution in tert-butanol(Δ0.08 mol of OsO₄ ×1⁻¹) is stirred at room temperature overnight in thedark (mixture surrounded by means of aluminium foil). After addition of130 mg (1 mmol) of Na₂ SO₃, the reaction solution is diluted with 30 mlof CH₂ Cl₂, 10 ml of NaCl solution and 10 ml of water. The CH₂ Cl₂ phaseis separated off, washed once with NaCl solution and water, dried overNa₂ SO₄, filtered and concentrated. The oily residue is purified bychromatography on 50 ml of silica gel 60 using, toluene andtoluene/ethyl acetate (8:2).

Yield: 140 mg (43.8% of theory)

R_(f) =0.18 (A₅)

Example XIV4,6-Bis-p-fluorophenyl-2-isopropyl-3-(p-trifluoromethyl)-benzoyl-5-pyridinecarbaldehyde##STR23##

A solution of 1.3 g (2.5 mmol) of4,6-bis-p-fluorophenyl-5-hydroxymethyl-2-isopropyl-3-(p-trifluoromethylphenyl)-(hydroxy)-methyl!-pyridine in 50 ml of CH₂ Cl₂is treated at RT with a mixture of 1 g (10 mmol) of Al₂ O₃ and 2.2 g (10mmol) of PCC and stirred overnight at RT. For working-up, silica gel isadded, the mixture is stirred at RT for 20 min, filtered through silicagel and washed with CH₂ Cl₂, and the filtrate is concentrated.

Yield: 1.04 g (82% of theory)

R_(f) =0.46 (toluene)

Example XV 4,6-Bis-p-fluorophenyl-2-isopropyl-3-{1-(4-fluoronaphthyl)}-(methoxy)methyl!-5-pyridinecarboxylate ##STR24##

A solution of 1 g (1.8 mmol) of methyl4,6-bis-p-fluorophenyl-2-isopropyl-3-{1-(4-fluoronaphthyl}-(hydroxy)methyl!-5-pyridinecarboxylate in 10 ml ofDMF is added dropwise under argon at -10° C. to a suspension of 55 mg ofNaH (80% ) in 20 ml of DMF and the mixture is stirred for 20 min. Asolution of 0.14 ml (2.3 mmol) of CH₃ I in 5 ml of DMF is then addeddropwise at -10° C. After stirring for 1 h, the mixture is slowly thawedand stirred at RT for 2 h. For working-up, it is treated with 20 ml of1N AcOH, extracted three times with ethyl acetate, and the combinedorganic phases are dried over Na₂ SO₄, filtered and concentrated. Theproduct is chromatographed on silica gel 60.

Yield: 0.95 g (95% of theory)

R_(f) =0.53 (toluene)

Example XVI 4,6-Bis-p-fluorophenyl-2-isopropyl-3-(p-trifluoromethyl-phenyl)(fluoro)methyl!5-pyrimidinecarbaldehyde##STR25##

9.0 g (17.5 mmol) of the compound 2,4-di-(4-fluorophenyl)-6-isopropyl-5-(p-trifluoromethylphenyl)-fluoromethyl!-3-hydroxymethyl-pyriline(Example 31) are stirred for 2 h at RT in 200 ml of CH₂ Cl₂ with 3.56 g(34.9 mmol) of Al₂ O₃ and 7.68 g (34.9 mmol) of PCC. Silica gel is thenadded, the mixture is stirred for 10 min and filtered through silicagel, the solid is washed with CH₂ Cl₂ and the filtrate is concentrated.

Yield: 7.49 g (84% of theory)

R_(f) =0.76 (toluene)

Example XVII Methyl 4,6-bis-p-fluorophenyl-2-isopropyl-3-(p-trifluoromethylphenyl)-(fluoro)methyl !-pyridine-5-ω-propenoate##STR26##

0.19 ml of diisopropylamine is treated at -78° C. in 10 ml of THF underargon with 0.78 ml of 1.6N (1.25 mmol) n-BuLi, and the mixture isstirred at 0° C. for 5 min, treated at -78° C. with 0.09 ml (1.1 mmol)of methyl acetate and stirred for 30 min. 0.40 g (0.78 mmol) of thecompound from Example XVI dissolved in 10 ml of THF is then addeddropwise. After stirring at -78° C. for 4 h, the mixture is thawedovernight. It is treated with NH₄ Cl solution and water with cooling andextracted twice with ethyl acetate. The combined organic phases aredried over sodium sulphate, concentrated and chromatographed on silicagel 60 (petroleum ether/ethyl acetate=10:1).

Yield: 0.11 g (25% of theory)

R_(f) =0.35 (petroleum ether/ethyl acetate=9:1)

Example XVIII4,6-Bis-p-fluorophenyl-2-isopropyl-3-p-trifluoromethylphenyl-benzoyl-5-pyridineacetaldehydemethyl enol ether ##STR27##

5.7 g (13.2 mmol) of methoxymethyl-triphenylphosphonium bromide/sodiumamide (Instant Ylide) are suspended in 100 ml of THF, stirred at RT for20 min, treated dropwise with a solution of 2.7 g (5.3 mmol) of thecompound from Example XIV in 50 ml of THF and stirred overnight. Forworking-up, the mixture is added to ice-water, extracted three timeswith CH₂ Cl₂, and the combined organic phases are dried, filtered,concentrated and chromatographed on silica gel 60 (petroleum ether/ethylacetate=9:1).

Yield: 1.0 g (35% of theory)

R_(f) =0.6 (petroleum ether/ethyl acetate=9:1)

Example XIX4,6-Bis-p-fluorophenyl-2-isopropyl-3-p-trifluoromethyl-benzoyl-5-pyridineacetaldehyde##STR28##

0.2 g (1.3 mmol) of NaI and 0.14 g (1.3 ml) of (CH₂)₃ SiCl is addedunder argon to a solution of 0.7 g (1.3 mmol) of the compound fromExample XVIII in 30 ml of CH₃ CN and the mixture is stirred at RT for 3h. After again adding the same amounts of NaI and Me₃ SiCl, it isstirred overnight. The mixture is then treated with saturated aqueousNa₂ SO₂ O₃ solution and extracted three times with ether, and thecombined organic phases are dried, concentrated and chromatographed onsilica gel 60 (petroleum ether/ethyl acetate=10:1).

Yield: 0.38 g (55% of theory)

R_(f) =0.55 (toluene)

PREPARATION EXAMPLES Example 14,6-Bis-(p-fluorophenyl)-5-hydroxymethyl-2-isopropyl-3-(p-trifluoromethylphenyl)-(hydroxy)-methyl!-pyridine ##STR29##

A solution of 2 g (3.7 mmol) of the compound from Example V in 10 ml ofTHF is added dropwise under argon at reflux to 11 ml of LiAlH₄ in THF (1molar solution) and the mixture is stirred for 1 h. For working-up, itis cooled to 0° C., treated with 20% strength aqueous Na K tartratesolution, diluted with water and extracted three times with ethylacetate. The combined organic phases are dried over Na₂ SO₄, filteredand concentrated, and the product is chromatographed on silica gel 60(toluene/ethyl acetate=9:1).

Yield: 1.38 g (73% of theory)

R_(f) =0.20 (toluene/ethyl acetate=9:1)

Example 24,6-Bis-(p-fluorophenyl)-5-hydroxymethyl-2-isopropyl-3-p-trifluoromethylbenzoylpyridine##STR30##

4 mg (0.10 mmol) of NaBH₄ are added at 0° C. to a suspension of 50 mg(0.1 mmol) of the compound from Example XIV in 10 ml of CH₃ OH and,after addition of 2 ml of dioxane, the mixture is stirred for 1 h. Forworking-up, it is acidified with 1N AcOH and extracted three times withethyl acetate, and the combined organic phases are dried over Na₂ SO₄,filtered and concentrated.

Yield: 48.3 mg (94% of theory)

R_(f) =0.39 (CH₂ Cl₂ /CH₃ OH=9:1)

Example 3 4,6-Bis-(p-fluorophenyl)-2-isopropyl-3-(p-trifluoromethylphenyl)-(fluoro)methyl!5-(1-hydroxyethyl)pyridine##STR31##

700 mg (1.36 mmol) of the compound from Example XVI are stirred underargon at -78° C. for 3 h with 0.54 ml (3M in THF, 1.63 mmol) ofmethylmagnesium bromide in 10 ml of THF. After addition of a further0.27 ml of 3M (0.81 mmol) CH₃ MgBr and stirring for 1 h, the mixture iswarmed, stirred for 1 h, treated with saturated aqueous NH₄ Cl solutionand CH₂ Cl₂, brought to pH 5 (1N HCl), shaken and separated. The aqueousphase is extracted again with CH₂ Cl₂, and the combined organic phasesare shaken with NaCl solution, dried over sodium sulphate andconcentrated.

Yield: 0.72 g (99.9% of theory)

R_(f) =0.36 (toluene)

Example 4 4,6-Bis-(p-fluorophenyl)-2-isopropyl-3-(p-trifluoromethylphenyl)-(fluoro)methyl!5-(3-hydroxy-1-propyl)pyridine##STR32##

79 mg (0.14 mmol) of the compound from Example XVII are treated with0.37 ml of 1M (0.37 mmol) LiAlH₄ solution in 4 ml of THF under argon atRT and the mixture is stirred for 30 min. It is then added to ice-water,adjusted to pH 3 using 1N HOAc and extracted three times with ethylacetate. The combined organic phases are dried over sodium sulphate,filtered and concentrated, and the residue is chromatographed on silicagel 60 (petroleum ether/ethyl acetate=3:1).

Yield: 0.034 g (46% of theory)

R_(f) =0.38 (petroleum ether 40:60: ethyl acetate=3:1)

Example 54,6-Bis-(p-fluorophenyl)-2-isopropyl-3-p-trifluoromethylbenzoyl-5-(2-hydroxy-1-ethyl)-pyridine ##STR33##

0.05 g (0.1 mmol) of the compound from Example XIX is suspended in 20 mlof EtOH and treated with 8 mg (0.2 mmol) of NaBH₄, and the mixture isstirred at RT for 2 h. It is then treated with water, adjusted to pH 5(1N AcOH) and extracted three times with ethyl acetate. The combinedorganic phases are dried, concentrated and chromatographed on silica gel60 (petroleum ether/ethyl acetate=3:1)

Yield: 0.03 g (65% of theory)

R_(f) =0.79 (petroleum ether/ethyl acetate=2:1)

The compounds listed in Tables 1-4 are prepared in analogy to theprocedures of Examples 1-5:

                  TABLE 1    ______________________________________    1 #STR34##    Ex.-No.          T                 Y         R.sub.f                                           Eluent    ______________________________________          2 #STR35##        o-CH.sub.3, p-F                                      0,61 A.sub.1    7          3 #STR36##        o-CH.sub.3, p-F                                      0,53 A.sub.2    8          4 #STR37##        p-F       0,51 A.sub.1    9          5 #STR38##        p-F       0,58 A.sub.1    10          6 #STR39##        p-F       0,51 A.sub.1    11          7 #STR40##        p-F       0,27 A.sub.1    12          8 #STR41##        p-F       0,47 A.sub.1    ______________________________________

                  TABLE 2    ______________________________________    9 #STR42##    Ex.-No.          T                 Y         R.sub.f                                           Eluent    ______________________________________    13          3 #STR43##        p-F       0,28 A.sub.3    14          3 #STR44##        m-CF.sub.3                                      0,58 A.sub.1    15          0 #STR45##        p-F       0,53 A.sub.1    16          0 #STR46##        m-CF.sub.3                                      0,51 A.sub.1    17          1 #STR47##        m-CF.sub.3                                      0,44 A.sub.1    18          5 #STR48##        p-F       0,56 A.sub.1    19          5 #STR49##        m-CF.sub.3                                      0,62 A.sub.1    20          6 #STR50##        p-F       0,57 A.sub.1    ______________________________________

                  TABLE 3    ______________________________________    2 #STR51##    Ex.-No.  D                 R.sub.f                                      Eluent    ______________________________________    21             3 #STR52##        0,39   A.sub.4    ______________________________________

                                      TABLE 4    __________________________________________________________________________    4 #STR53##    Ex.-No.        T             L  D           R.sub.f                                        Eluent    __________________________________________________________________________    22        4 #STR54##    iPr                         5 #STR55##  0,37                                        A.sub.1    23        5 #STR56##    iPr                         5 #STR57##  0,35                                        A.sub.5    24        6 #STR58##    iPr                         5 #STR59##  0,64                                        A.sub.6    25        3 #STR60##    iPr                         6 #STR61##  0,28                                        A.sub.2    26        3 #STR62##    cPent                         6 #STR63##  0,60                                        A.sub.1    27        4 #STR64##    iPr                         6 #STR65##  0,51                                        A.sub.1    28        7 #STR66##    iPr                         6 #STR67##  0,28                                        A.sub.3    29        6 #STR68##    iPr                         6 #STR69##  0,48                                        A.sub.1    30        6 #STR70##    cPent                         6 #STR71##  0,53                                        A.sub.1    __________________________________________________________________________

Example 31 2-,4-di-(4-Fluorophenyl)-6-isopropyl-5-4-(trifluoromethylphenyl)-fluoromethyl!-3-hydroxymethyl-pyridine##STR72##

Under argon, a mixture of 23.04 mg (0.607 mmol; 1.1 eq.) of LiAlH₄ and 5ml of THF p.a. is warmed to 60° C. to 80° C. and 0.3 g (0.552 mmol) ofthe compound from Example VI dissolved in 5 ml of THF is allowed to runin dropwise. The mixture is then boiled under reflux for 1 h. Aftercooling to 0° C., 5 ml of a 20% strength potassium sodium tartratesolution and 10 ml of water are added and the mixture is extracted twicewith 80 ml of ethyl acetate each time. The combined organic phases arewashed once with saturated NaCl solution, dried over Na₂ SO₄ andconcentrated in vacuo. The residue is chromatographed on 60 g of silicagel 60 first using toluene and then using toluene/ethyl acetate (9:1).

Yield: 156 mg (54.9% of theory)

R_(f) =0.53 (toluene/ethyl acetate 9:1)

Example 322,4-di-(4-Fluorophenyl)-6-isopropyl-5-(4-(trifluoromethylbenzyl)-3-hydroxymethyl-pyridine##STR73##

11.2 mg (0.295 mmol; 3.0 eq.) of LiAlH₄ are suspended under argon in 2ml of THF p.a. at 80° C. 55 mg (0.0982 mmol) of the compound fromExample VII in 2 ml of THF p.a. are added dropwise at 80° C. Afterstirring at 80° C. for 8 h, the solution is cooled to 20° C, treatedwith 5 ml of 20% strength potassium sodium tartrate solution, extractedtwice with 20 ml of ethyl acetate and dried over NA₂ SO₄, and theorganic phase is concentrated. The residue is purified by silica gelchromatography using toluene.

Yield: 36 mg (73.0% of theory)

R_(f) =0.58 (toluene/ethyl acetate 9:1)

Example 33 2,4-di-(4-Fluorophenyl)-6-isopropyl-5-4-(trifluoromethylphenyl)-aminomethyl!-3-hydroxymethyl-pyridine##STR74##

90 mg (0.167 mmol) of the compound from Example IX are dissolved underargon in 5 ml of toluene p.a. at -78° C. and 0.84 ml (1 mmol; 6 eq.) ofdiisobutylaluminium hydride (DIBAL-H; 1.2 molar in toluene) is addedfrom a syringe. The mixture is stirred for a further 15 min at -78° C.and the reaction solution is then stored at -30° C. overnight. It isthen cooled to -78° C., 2 ml of 20% strength potassium sodium tartratesolution are added and the mixture is diluted with toluene. The solutionis washed once with saturated NaCl solution, dried over Na₂ SO₄ andconcentrated. The residue is purified by chromatography on silica gel(40 g) using toluene and toluene/ethyl acetate (8:2).

Yield: 60 mg (70.3% of theory)

R_(f) =0.27 (A₁₁)

Example 34 2,4-di-(4-Fluorophenyl)-6-cyclopentyl-5-2-(benzothiazol-2-yl)-fluoromethyl!-3-hydroxymethyl-pyridine ##STR75##

According to Example 31, 450 mg (0.9 mmol) of the compound from ExampleXI are reduced to the alcohol using 44.4 mg (1.171 mmol; 1.3 eq) ofLiAlH₄ in 30 ml of THF.

Yield: 182 mg (42.6% of theory)

R_(f) =0.45 (toluene/ethyl acetate 9:1)

The compounds listed in Tables 5-8 are prepared according to theprocedures indicated above:

                                      TABLE 5    __________________________________________________________________________    1 #STR76##    Ex.-No. E             R.sup.18                               Z.sup.1 /Z.sup.2 L           R.sub.f    __________________________________________________________________________                                                            (eluent)    35            2 #STR77##    F    p-CF.sub.3 /H                                                3 #STR78##  0,2 (A.sub.7)    36            4 #STR79##    F    p-CF.sub.3 /H                                                3 #STR80##  0,44 (A.sub.4)    37            4 #STR81##    F    p-CF.sub.3 /H                                                5 #STR82##  0,57 (A.sub.5)    38            6 #STR83##    F    p-CF.sub.3 /H                                                5 #STR84##  0,23 (A.sub.7)    39            6 #STR85##    H    p-CF.sub.3 /H                                                5 #STR86##  0,22 (A.sub.7)    40            7 #STR87##    F                               8 #STR88##                                                5 #STR89##  0,26 (A.sub.7)    41            7 #STR90##    H    p-CF.sub.3 /H                                                5 #STR91##  0,30 (A.sub.5)    42 Racemat            7 #STR92##    F    p-CF.sub.3 /H                                                5 #STR93##  0,6 (A.sub.5)    43 Enantiomer I            7 #STR94##    F    p-CF.sub.3 /H                                                5 #STR95##  0,6 (A.sub.5)    44 Enantiomer II            7 #STR96##    F    p-CF.sub.3 /H                                                5 #STR97##  0,6 (A.sub.5)    45            7 #STR98##    F    p-CF.sub.3 O--/H                                                5 #STR99##  0,41 (A.sub.5)    46            7 #STR100##   F    o,p-(CF.sub.3).sub.2                                                5 #STR101## 0,60 (A.sub.5)    47            7 #STR102##   F    p-CF.sub.3 /H                                                9 #STR103## 0,67 (A.sub.5)    48            7 #STR104##   F    p-CF.sub.3 /H                                                0 #STR105## 0,59 (A.sub.5)    49            7 #STR106##   F    o,p(CF.sub.3).sub.2                                                0 #STR107## 0,43 (A.sub.5)    50            7 #STR108##   F    p-CF.sub.3 /H                                                1 #STR109## 0,29 (A.sub.7)    51            7 #STR110##   F    p-CF.sub.3 /H                                                2 #STR111## 0,54 (A.sub.5)    52            7 #STR112##   F    p-CF.sub.3 /H                                                3 #STR113## 0,33 (A.sub.7)    53            7 #STR114##   F    p-CF.sub.3 /H                                                4 #STR115## 0,57 (A.sub.5)    54            7 #STR116##   H    p-f/H                                                3 #STR117## 0,48 (A.sub.5)    55            7 #STR118##   F    p-CF.sub.3 /H                                                3 #STR119## 0,53 (A.sub.5)    56            7 #STR120##   F    p-CF.sub.3 O--/H                                                3 #STR121## 0,26 (A.sub.4)    57            7 #STR122##   F    p-Ph/H                                                3 #STR123## 0,51 (A.sub.5)    58            7 #STR124##   F    3,5-(CF.sub.3).sub.2                                                3 #STR125## 0,67 (A.sub.5)    59            7 #STR126##   F    m-CF.sub.3 O--/H                                                3 #STR127## 0,26 (A.sub.4)    60            7 #STR128##   H    m-Phe/H                                                3 #STR129## 0,51 (A.sub.5)    61            7 #STR130##   F    m-Phe/H                                                3 #STR131## 0,62 (A.sub.5)    62            7 #STR132##   OH   m-Phe/H                                                3 #STR133## 0,27    __________________________________________________________________________                                                            (A.sub.5)

                  TABLE 6    ______________________________________    8 #STR134##    Ex.-No.     Z          R.sup.19                                  R.sub.f (LM)    ______________________________________    63          m-Cl       H      0,68 (A.sub.5)    64          m-Cl       F      0,62 (A.sub.5)    65          m-CH.sub.3 F      0,59 (A.sub.5)    ______________________________________

                  TABLE 7    ______________________________________    9 #STR135##    Ex.-No.           R.sup.20                  R.sup.21      L         R.sub.f (eluent)    ______________________________________    66     F      2-Naphthyl                                0 #STR136##                                          0,59 (A.sub.5)    67     F      1-Naphthyl                                0 #STR137##                                          0,57 (A.sub.5)    68     F      2-Napthyl                                1 #STR138##                                          0,5 (A.sub.5)    69     F      1-Naphthyl                                1 #STR139##                                          0.76 (A.sub.5)    70     F      2-Naphthyl                                2 #STR140##                                          0,80 (A.sub.5)    71     OH     2-Naphthyl                                3 #STR141##                                          0,52 (A.sub.5)    72     F      1-Naphthyl                                4 #STR142##                                          0,55 (A.sub.5)    73     F      2-Naphthyl                                4 #STR143##                                          0,60 (A.sub.5)    74     F      5-CF.sub.3 -Naphthyl-1                                1 #STR144##                                          0,33 (A.sub.4)    75     H      5-CF.sub.3 -Naphthyl-1                                1 #STR145##                                          0,2 (A.sub.4)    76     F      5-CF.sub.3 -Naphthyl-1                                0 #STR146##                                          0,24 (A.sub.7)    77     OH     6-CH.sub.3 O-Naphthyl-2                                1 #STR147##                                          0,29 (A.sub.5)    ______________________________________

                  TABLE 8    ______________________________________    5 #STR148##                                           R.sub.f    Ex.-No.          R.sup.22                 R.sup.23         L        (eluent)    ______________________________________    78    F                 6 #STR149##                                  1 #STR150##                                           0,44 (A.sub.5)    79    F                 7 #STR151##                                  0 #STR152##                                           0,18 (A.sub.5)    80    H                 7 #STR153##                                  0 #STR154##                                           0,13 (A.sub.5)    81    F                 8 #STR155##                                  0 #STR156##                                           0,37 (A.sub.5)    82    F                 9 #STR157##                                  0 #STR158##                                           0,62 (A.sub.5)    ______________________________________

Example 83 2,4-di-(4-Fluorophenyl)-6-isopropyl-5-2-(3-trifluoromethylphenyl)vinyl!-3-hydroxymethyl-pyridine ##STR159##

Under argon, 3.0 mml (3 mol; 6 eq.) of DIBAL-H are added to a solutionof 269 mg (0.5 mmol) of the compound from Example XII in 10 g of drytoluene at -78° C. and the mixture is then stirred without a coolingbath for 4 h to +15° C. 40 ml of ethyl acetate and 20 ml of a 20%strength potassium sodium tartrate solution are added and the mixture isstirred for 10 min. The aqueous phase is separated off, and the organiclayer is dried over Na₂ SO₄, filtered and concentrated.

Yield: 250 mg (98% of theory)

R_(f) =0.38 (A₄)

Example 84 2,4-di-(4-Fluorophenyl)-6-isopropyl-5-2-(3-trifluoromethylphenyl)ethyl!-3-hydroxy-methyl-pyridine ##STR160##

100 mg (0.196 mmol) of the compound from Example 83 are stirred at roomtemperature overnight in 20 g of methanol in the presence of 100 mg ofPd/C (10% ) under a hydrogen atmosphere. The catalyst is then filteredoff with suction through SiO₂ and washed with methanol, and the filtrateis concentrated. The residue is purified on 30 ml of silica gel by flashchromatography using toluene.

Yield: 71 mg (70.1% of theory)

R_(f) =0.25 (A₄)

Example 85 2,4-di-(4-Fluorophenyl)-6-isopropyl-5-2-(3-trifluoromethyl-phenyl)-1,2-dihydroxyethyl!-3-hydroxymethyl-pyridine##STR161##

Analogously to Example 33, 76 mg (0.133 mmol) of the compound fromExample XIII are reacted with 0.33 ml (0.333 mmol, 2.5 eq.) of DIBAL-H(1 molar in toluene).

Yield: 31 mg (43% of theory)

R_(f) =0.16 (toluene/ethyl acetate 8:2)

The compounds listed in Tables 9 and 10 are prepared according to theseprocedures:

                  TABLE 9    ______________________________________    5 #STR162##    Ex.-No.           T                        R.sub.f (eluent)    ______________________________________    86           6 #STR163##              0,24 (A.sub.5)    87           7 #STR164##              0,58 (A.sub.5)    88           8 #STR165##              0,18 (A.sub.4)    89           9 #STR166##              0,21 (A.sub.5)    90           0 #STR167##              0,09 (A.sub.8)    91           1 #STR168##              0,59 (A.sub.5)    92           2 #STR169##              0,55 (A.sub.5)    93           3 #STR170##              0,56 (A.sub.5)    94           4 #STR171##              0,45 (A.sub.9)    95 (E-Isomer)           5 #STR172##              0,58 (A.sub.5)    96 (Z-Isomer)           5 #STR173##              0,73 (A.sub.5)    97           6 #STR174##              0,31 (A.sub.10)    98           7 #STR175##              0,27 (A.sub.10)    99           8 #STR176##              0,33 (A.sub.4)    100           9 #STR177##              0,15 (A.sub.4)    101           0 #STR178##              0,13 (A.sub.5)    102           1 #STR179##              0,51 (A.sub.11)    103           2 #STR180##              0,36 (A.sub.5)    ______________________________________

                                      TABLE 10    __________________________________________________________________________    Ex. No.        Structure                   R.sub.f (eluent)    __________________________________________________________________________    104        1 #STR181##                 0.55 (Tol/EA = 9:1)    105        2 #STR182##                 0.39 (PE/EA = 85:15)    106        3 #STR183##                 0.46 (PE/EA = 85:15)    107        4 #STR184##                 0.19 (PE/EA = 9:1)    108        5 #STR185##                 0.2 (PE/EA = 9:1)    109        6 #STR186##                 0.70 (Tol/EA = 9:1)    110        7 #STR187##                 0.22 (PE/EA = 8:2)    111        8 #STR188##                 0.32 (PE/EA 8:2)    112        9 #STR189##                 0.27 (PE:EA 8:2)    113        0 #STR190##                 0.29 (PE/EA 8:2)    114        1 #STR191##                 0.26 (PE/EA 8:2)    115        2 #STR192##                 0.34 (PE/EA 84:15)    116        3 #STR193##                 0.36 (PE/EA 9:1)    117        4 #STR194##                 0.18 (PE/EA 85:15)    118        5 #STR195##                 0.26 (PE/EA 84:15)    119        6 #STR196##                 0.29 (PE/EA 84:15)    120        7 #STR197##                 0.07 (PE/EA 9:1)    __________________________________________________________________________

We claim:
 1. A 2-Aryl-substituted pyridine of the formula (I) ##STR198##in which A and E are identical or different and represent aryl having 6to 10 carbon atoms, which is optionally substituted up to 3 timesidentically or differently by halogen, hydroxyl, trifluoromethyl,trifluoromethoxy or by straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy each having up to 7 carbon atoms, or by a groupof the formula --NR¹ R²,in which R¹ and R² are identical or differentand denote hydrogen, phenyl or straight-chain or branched alkyl havingup to 6 carbon atoms, D represents straight-chain or branched alkylhaving up to 8 carbon atoms, which is substituted by hydroxyl, Lrepresents cycloalkyl having 3 to 8 carbon atoms or straight-chain orbranched alkyl having up to 8 carbon atoms, which is optionallysubstituted by cycloalkyl having 3 to 8 carbon atoms or by hydroxyl, Trepresents a radical of the formula ##STR199## in which R³ and R⁴ areidentical or different and denote cycloalkyl having 3 to 8 carbon atoms,ordenote aryl having 6 to 10 carbon atoms, which is optionallysubstituted up to 3 times identically or differently by trifluoromethyl,trifluoromethoxy, halogen, hydroxyl, carboxyl, nitro, by straight-chainor branched alkyl, acyl, alkoxy or alkoxycarbonyl each having up to 6carbon atoms or by phenyl, phenoxy or phenylthio, which for their partcan be substituted by halogen, trifluoromethyl or trifluoromethoxy,and/or the aryl is optionally substituted by a group of the formula--NR⁷ R⁸,in which R⁷ and R⁸ are identical or different and have themeaning of R¹ and R² indicated above, X denotes straight-chain orbranched alkylene or alkenylene each having up to 10 carbon atoms, eachof which is optionally substituted up to 2 times by hydroxyl or halogen,R⁵ denotes hydrogen and R⁶ denotes hydrogen, mercapto, halogen, azido,trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branchedalkoxy having up to 5 carbon atoms or a radical of the formula --NR⁹R¹⁰,in which R⁹ and R¹⁰ are identical or different and have the meaningof R¹ and R² indicated above,or R⁵ and R⁶ together with the carbon atomform a carbonyl group,or a salt thereof.
 2. A 2-Aryl-substitutedpyridine of the formula according to claim 1, in whichA and E areidentical or different and represent phenyl or naphthyl, each of whichis optionally substituted up to 2 times identically or differently byfluorine, chlorine, bromine, hydroxyl, trifluoromethyl,trifluoromethoxy, nitro or by straight-chain or branched alkyl, acyl oralkoxy each having up to 6 carbon atoms or by a group of the formula--NR¹ R²,in which R¹ and R² are identical or different and denotehydrogen, phenyl or straight-chain or branched alkyl having up to 4carbon atoms, D represents straight-chain or branched alkyl having up to7 carbon atoms, which is substituted by hydroxyl, L representscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl,orrepresents straight-chain or branched alkyl having up to 6 carbonatoms, which is optionally substituted by cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or by hydroxyl, T represents aradical of the formula ##STR200## in which R³ and R⁴ are identical ordifferent and denote cyclopropyl, cyclopentyl or cyclohexyl, or denotenaphthyl, or phenyl, which are optionally substituted up to 3 timesidentically or differently by trifluoromethyl, trifluoromethyoxy,fluorine, chlorine, bromine, hydroxyl, carboxyl, by straight-chain orbranched alkyl, acyl, alkoxy or alkoxycarbonyl each having up to 5carbon atoms or by phenyl, phenoxy or phenylthio, which for their partcan be substituted by fluorine, chlorine, bromine, trifluoromethyl ortrifluoromethoxy,and/or when R³ and R⁴ are phenyl or naphthyl, thenthese are optionally substituted by a group of the formula --NR⁷ R⁸, inwhich R⁷ and R⁸ are identical or different and have the meaning of R¹and R⁸ indicated above, X is straight-chain or branched alkylene oralkenylene each having up to 8 carbon atoms, each of which is optionallysubstituted up to 2 times by hydroxyl or fluorine, R⁵ denotes hydrogenand R⁶ denotes hydrogen, fluorine, chlorine, bromine, azido,trifluoromethyl, hydroxyl, mercapto, trifluoromethoxy, straight-chain orbranched alkoxy having up to 4 carbon atoms or a radical of the formula--NR⁹ R¹⁰,in which R⁹ and R¹⁰ are identical or different and have themeaning of R¹ and R² indicated above,or R⁵ and R⁶ together with thecarbon atom form a carbonyl group, or a salt thereof.
 3. A2-Aryl-substituted pyridine of the formula according to claim 1, inwhichA and E are identical or different and represent phenyl ornaphthyl, each of which is optionally substituted up to 2 timesidentically or differently by fluorine, chlorine, bromine, hydroxyl,trifluoromethyl, trifluoromethoxy, nitro or by straight-chain orbranched alkyl or alkoxy each having up to 5 carbon atoms, D representsstraight-chain or branched alkyl having up to 6 carbon atoms, which issubstituted by hydroxyl, L represents cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl, orrepresents straight-chain orbranched alkyl having up to 5 carbon atoms, which is optionallysubstituted by cyclopentyl or cyclohexyl, T represents a radical of theformula ##STR201## in which R³ and R⁴ are identical or different anddenote cyclopropyl, or denote phenyl, which is optionally substituted upto 2 times identically or differently by trifluoromethyl,trifluoromethyoxy, fluorine, chlorine, bromine, hydroxyl, carboxyl,anino by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl eachhaving up to 4 carbon atoms or by phenyl, phenoxy or phenylthio, whichfor their part can be substituted by fluorine, chlorine, bromine,trifluoromethyl or trifluoromethoxy, X denotes straight-chain orbranched alkylene or alkenylene each having up to 6 carbon atoms, eachof which is optionally substituted up to 2 times by hydroxyl orfluorine, R⁵ denotes hydrogen and R⁶ denotes hydrogen, fluorine,chlorine, bromine, azido, amino, trifluoromethyl, hydroxyl,trifluoromethoxy, methoxy or mercapto,or R⁵ and R⁶ together with thecarbon atom form a carbonyl group, or a salt thereof.
 4. A2-Aryl-substituted pyridine of the formula according to claim 1, inwhichA represents phenyl, which is optionally substituted up to 2 timesidentically or differently by fluorine, chlorine, methyl, nitro ormethoxy.
 5. Pharmaceutical composition which comprises ananti-arteriosclerotic effective amount of a 2-substituted pyridineaccording to claim 1 and a pharmacologically acceptable formulationauxiliary.
 6. A method of treating arteriosclerosis in a patient in needthereof which comprises administering to such a patient an amounteffective therefor of a compound or salt thereof according to claim 1.